We propose to investigate the hypothesis that ischemia-induced degeneration of neurons in the retina, a clinical condition frequently leading to blindness, is mediated by the endogenous excitatory amino acids (EAA), glutamate and aspartate. These compounds are major excitatory transmitters in the retina and also have potent neurotoxic (excitotoxic) activity which is mediated by EAA synaptic receptors. Several EAA receptor subtypes have been identified and, recently, new classes of potent EAA antagonists have been discovered. Several lines of evidence suggest that endogenous EAA may cause or that EAA antagonists can prevent neuronal damage associated with anoxia/ischemia. However, evidence for in vivo protection against anoxic/ischemic brain damage is rather tenuous because of inadequacies inherent in the animal models available for such studies. The retina lends itself to both in vitro and in vivo studies of ischemic neuronal degeneration. We have developed an oxygen/glucose deprivation model for studying ischemic neuronal degeneration in the isolated (ex vivo) chick embryo retina and propose to screen various EAA antagonists (anti-excitotoxins) for their ability to prevent such degeneration in this model. We have developed a model for reproducibly inducing a similar pattern of acute neuronal degeneration in the in vivo adult rat retina by using a rose bengal dye/photothrombosis approach to occlude the retinal vasculature. We are now developing a model of delayed neuronal degeneration in the in vivo adult rat retina using an intraocular hypertension approach. We propose to continue developing the latter model, to utilize both rodent models to study mechanisms of ischemic retinal degeneration, and to systematically evaluate anti-excitotoxic drugs found effective in protecting the isolated chick retina against ischemic degeneration for their ability to protect against acute and delayed ischemic damage in the in vivo rat retina.